Antimalarials

• Causes of malaria:

  • Plasmodium falciparum
  • P. vivax
  • P. ovale
  • P. malariae
  • P. knowlesi
• Antimalarial control methods include:

  • Vaccines: e.g. RTS,S/AS01; R21/Matrix-M (2023)
  • Bednets
  • Window and door screening
  • Repellents
  • Antiprotozoals
• Classification of Antimalarial Agents:

  1. Tissue Schizontocidal Drugs

  2. Blood Schizontocidal Drugs

  3. Gametocytocidal drugs: Destroy sexual erythrocytes preventing transmission to mosquito

  4. Sporontocidal drugs: Prevent formation of oocyst and sporozoites in mosquito
• Tissue schizonticide: Primaquine

  • Eradicates primary exoerythrocytic forms of P. falciparum and P. vivax
  • Only agent for radical cures of P. vivax and P. ovale malarias
  • Destroys sexual (gametocytic) forms of all four plasmodia
  • Not effective against the asexual erythrocytic stage of malaria
• Tissue schizonticide: Primaquine

  • Mechanism of action: Metabolites act as oxidants responsible for schizonticidal action, hemolysis, and methemoglobinemia
  • Clinical uses: Therapy (Radical Cure) of acute vivax and ovale malaria, Terminal Prophylaxis of vivax and ovale malaria, Chemoprophylaxis of malaria, Gametocytocidal action
• Tissue schizonticide: Primaquine

  • Adverse effects: Low incidence except for drug-induced hemolytic anemia in G6PD deficient patients, abdominal discomfort, methemoglobinemia, granulocytopenia, agranulocytosis, contraindicated during pregnancy
• Blood schizonticide: Chloroquine

  • Highly specific for the asexual form
  • Drug of choice in treating erythrocytic P. falciparum malaria, except in resistant strains
  • Clinical uses: Treatment of nonfalciparum and sensitive falciparum malaria, Chemoprophylaxis in malarious regions without resistant falciparum malaria, Amebic liver abscess
• Blood schizonticide: Chloroquine

  • Mechanism of action: Binds to heme, preventing polymerization to hemozoin
  • Pharmacokinetics: Rapidly absorbed, concentrates in various tissues, large volume of distribution, metabolized by hepatic system
  • Adverse effects: Minimal at low doses, GI upset, pruritus, headaches, blurring of vision, ECG changes, discoloration of nail beds and mucous membranes
• Blood schizonticide: Chloroquine

  • Resistance: Chloroquine-resistant P. falciparum exhibit multigenic alterations that confer high resistance
• Blood schizonticide: Amodiaquine
• Amodiaquine:

  • Closely related to chloroquine
  • Widely used to treat malaria due to low cost, limited toxicity, and effectiveness against chloroquine-resistant P. falciparum
  • Rare toxicities include agranulocytosis, aplastic anemia, and hepatotoxicity
  • WHO recommends using amodiaquine plus artesunate or amodiaquine plus sulfadoxine-pyrimethamine as an interim alternative
• Mefloquine:

  • Effective against multidrug-resistant forms of P. falciparum
  • Mechanism of action similar to quinine, damaging parasite's membrane
  • Resistant strains identified
  • Well absorbed orally, concentrates in liver and lung
  • Long half-life of 17 days
  • Adverse reactions include nausea, vomiting, dizziness, disorientation, hallucinations, depression
  • Possible ECG abnormalities and cardiac arrest if taken with quinine or quinidine
• Quinine and Quinidine:

  • Interfere with heme polymerization
  • Reserved for severe malaria and resistant malarial strains
  • Major adverse effect is cinchonism causing nausea, vomiting, tinnitus, vertigo
  • Drug interactions include potentiation of neuromuscular-blocking agents and elevation of digoxin levels
  • Retarded absorption when taken with aluminum-containing antacids
  • High doses may terminate pregnancy and cause fetal abnormalities
• Artemisinin:

  • Derived from qinghaosu plant
  • Used for severe and multidrug-resistant P. falciparum malaria
  • Produces free radicals within plasmodium food vacuole
  • Metabolized in the liver, excreted in bile
  • Adverse effects include nausea, vomiting, diarrhea
  • Major derivatives are Arthemeter and Artesunate
• Artemisinin Resistance:

  • No documented resistance historically
  • Reduced parasite susceptibility observed in some regions due to fake antimalarials and poor quality self-medication
  • Significant reduction in parasite clearance rate with artemisinins in certain areas
  • Possible reasons include reduced killing of ring-stage parasites, quiescence, and SNPs on chromosome 13
• Pyrimethamine:

  • Blood schizonticide and sporonticide
  • Inhibits plasmodial dihydrofolate reductase
  • Used in combination with sulfonamide against Toxoplasma gondii
  • Megaloblastic anemia reversed with leucovorin
• Proguanil:

  • Metabolized to active metabolite cycloguanil
  • Selectively inhibits dihydrofolate reductase
  • Slow antimalarial action
  • Used with chloroquine as prophylaxis or with atovaquone as prophylaxis (Malarone)
  • Considered safe for use during pregnancy
• Antibiotics:

  • Modestly active antimalarials
  • Tetracycline and doxycycline active against erythrocytic schizonts
  • Doxycycline commonly used in falciparum malaria treatment in conjunction with quinine or quinidine
  • Clindamycin slowly active against erythrocytic schizonts, used in children and pregnant women
• Halofantrine & Lumefantrine:

  • Halofantrine effective against erythrocytic stages of all human malaria species
  • Lumefantrine available in fixed dose combination with artemether as Coartem, effective for P. falciparum infections